Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid and Their Relation to Response to Therapy of Childhood-Onset Systemic Lupus Erythematosus

Anna Carmela P. Sagcal-Gironella, Tsuyoshi Fukuda, Kristina Wiers, Shareen Cox, Shannen Nelson, Blair Dina, Catherine M.T. Sherwin, Marisa S. Klein-Gitelman, Alexander A. Vinks, Hermine I. Brunner*

*Corresponding author for this work

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Objectives: Mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF), which is currently used off-label as immunosuppressive therapy in childhood-onset SLE (cSLE). The objectives of this study were to (1) characterize the pharmacokinetics (MPA-PK) and pharmacodynamics (MPA-PD) of MPA and (2) explore the relationship between MPA-PK and cSLE disease activity. Methods: MPA-PK [area under the curve from 0-12 hours (AUC0-12)] and MPA-PD [inosine-monophosphate dehydrogenase (IMPDH) activity] were evaluated in cSLE patients on stable MMF dosing. Change in SLE disease activity while on MMF therapy was measured using the British Isles Lupus Assessment Group (BILAG) index. Results: A total of 19 AUC0-12 and 10 IMPDH activity profiles were included in the analysis. Large interpatient variability in MPA exposure (AUC0-12) was observed (mean ± SE: 32 ± 4.2 mg h/L; coefficient of variation: 57%). Maximum MPA serum concentrations coincided with maximum IMPDH inhibition. AUC0-12 and weight-adjusted MMF dosing were only moderately correlated (r = 0.56, P = 0.01). An AUC0-12 of ≥30 mg h/L was associated with decreased BILAG scores while on MMF therapy (P = 0.002). Conclusion: Weight-adjusted MMF dosing alone does not reliably allow for the prediction of exposure to biologically active MPA in cSLE. Individualized dosing considering MPA-PK appears warranted as this allows for better estimation of immunologic suppression (IMPDH activity). Additional controlled studies are necessary to confirm that an MPA AUC0-12 of at least 30 mg h/L is required for cSLE improvement.

Original languageEnglish (US)
Pages (from-to)307-313
Number of pages7
JournalSeminars in Arthritis and Rheumatism
Volume40
Issue number4
DOIs
StatePublished - Feb 2011

Keywords

  • Inosine 5'-monophosphate dehydrogenase (IMPDH)
  • Mycophenolic acid
  • Pharmacodynamics
  • Pharmacokinetics
  • Systemic lupus erythematosus

ASJC Scopus subject areas

  • Rheumatology
  • Anesthesiology and Pain Medicine

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